Several previous studies have shown that hyperestrogenism induced by endocrine disorders may be a major risk factor for breast cancer. However, obesity, family history, radiation exposure, and other factors are associated with breast cancer. To date, all the evidence available on breast cancer and PRL-secreting PitNETs has been from retrospective analyses or case reports.

The influence of PRL on breast cancer remains a subject of debate: some studies have shown that prolactin levels are not significantly higher in patients with breast cancer than in control individuals. One study reported a standardized mortality ratio of 1.07 (95% confidence interval: 0.5–2.03) among 1.342 patients with breast cancer who received treatment for hyperprolactinemia [12]. Another study involving 1,400 patients revealed that prolactin was associated with the occurrence of breast cancer, especially in postmenopausal women (relative risk: 1.37, p < 0.05) and in patients with ER + status (relative risk: 1.28, 95% confidence interval: 1.07–1.54, p = 0.003) [9].

PRL and estrogens play very important roles in normal mammary gland growth and development. The theory of PRL as a causative factor in breast cancer was initially suggested on the basis of studies that included mouse models. High circulating levels of PRL increase the synthesis and expression of PLRr in malignant mammary tissue, increasing DNA synthesis in breast cancer cells [13].

Other studies have evaluated the associations between PRL levels and several well-confirmed breast cancer risk factors, such as parity and age at menarche. Overall, lower exposure to estrogens and androgens in premenopausal women is hypothesized to decrease breast cancer risk. A strong association was found between PRL-secreting PitNETs and a family history of breast cancer [14, 15].

Cases of breast cancer were reported both in women and men. We identified 15 cases of breast cancer in patients with prolactinoma, 7 in men and 8 in women. In the majority of cases, we observed a latency period of diagnosis of several years, up to 36 years, and in almost all cases, the pituitary tumor was first diagnosed. Histopathological analysis revealed that the majority of patients were diagnosed with invasive ductal carcinoma with positive immunostaining for estrogen and progesterone receptors. One case with neuroendocrine differentiation of a unilateral breast tumor was reported in a 40 year-old female with positive immunostaining for PRLr.

Benign breast disease is a major risk factor that doubles the risk of subsequent breast cancer. Data show that the increase in risk is sustained and for 20 years after diagnosis and also, women who had a proliferative benign disease have a higher long-term risk than those with non-proliferative disease. Other studies show a 70% higher risk of breast cancer in patients with prior breast disease, than those without [16] PLRrs are a major mediator of the cellular effects of PRL. The Jak-STAT, Ras-MAPK, and PI3K-Akt pathways are the major mechanisms that mediate the effects of PRL [17]. PRL activates the Ras-Raf-MAPK pathway in mammary tumor cell lines, which signals cell proliferation [18]. Additionally, PRL activates other MAPKs, such as JNK, which impact proliferation and apoptosis [19,20,21]. Other kinases, such as c-Src, are activated in response to PRL and interact with PRLr-mediated signaling [22].

There are various isoforms of PRLr in various species. The expression of PRLr has been studied in normal, benign, and malignant breast tissue, and one immunohistochemical study that evaluated paraffin wax-embedded sections of 102 breast biopsies revealed that the receptor was expressed in more than two-thirds of female breast carcinomas and that positivity was correlated with moderate and strong staining for the ER in tissue sections [23]. Additionally, positive expression of PRLr was correlated with prognosis. In one study that evaluated the immunohistochemical analysis of PRLr protein expression levels via a tissue microarray of 102 cases, PRLr expression was found to be significantly downregulated in invasive breast cancer and was associated with lymph node negativity and low-grade well-differentiated tumors [24]. PRLr was found to be an independent predictor of favorable prognosis in human breast cancer patients.

Multiple promoters control human PRLr expression at the transcriptional level. Each promoter directs transcription/expression of a specific non-coding exon 1, a common non-coding exon 2, and coding exons E3-11. The identification of exon 11 of PRLR led to the discovery of alternative spliced products and two novel short forms (SF) that can inhibit the long form (LF) of PRLr activity, which is relevant in physiological regulation and breast cancer.

Constitutive LF and SF homodimers and heterodimers. Both forms, as dimers, are capable of ligand binding and PRL-induced phosphorylation of JAK2, but only LF can activate downstream STAT5 signaling.

Male breast cancer is a rare form of breast cancer, data from the literature show that the risk rises with age [25]. Prospective studies and clinical trials on breast cancer treatments have often excluded male participants. It seems that 15%–20% of patients have a family history of breast or ovarian cancer, and approximately 10% of the patients have a genetic predisposition. BRCA2 and Klinefelter’s syndrome were associated with an increased risk of male breast cancer [26]. We searched the literature and we found 7 cases reported in male patients diagnosed with prolactinoma. Hyperprolactinemia occurred before the diagnosis or concurrent with the diagnosis of breast cancer in all cases.

The role of estrogen in breast cancer has been deeply studied, but the role of testosterone has not been established. One proposed theory is that excess circulating testosterone can be aromatized into estrogen, which has been shown to increase human prolactin receptor gene expression within the peripheral tissues, which in turn directly stimulates breast tumor cell proliferation [27, 28].

Transgenic male mice that were treated with the mammary-selective, estrogen-insensitive promoter neu-related lipocalin (NRL), which drives PRL expression, and did not develop mammary tumors. However, in cooperation with transforming growth factor-α (TGF-α), PRL mammary tumors were induced in 100% of male bitransgenic mice. Similar to disease in human males, these tumors expressed variable levels of ER α and androgen receptors. Male breast tumors demonstrate high levels of ER α expression, similar to those in postmenopausal women. Like female patients, male patients exhibit resistance to antiestrogens, such as tamoxifen, or develop resistance after treatment. In vivo, PRL in combination with TGF-α induces ER α-positive, but estrogen-insensitive, disease [29,30,31].

Another association was observed between invasive breast cancer risk in postmenopausal women with high circulating PRL, particularly for ER-positive disease. Also, PRL/PRLR is expressed in 95% of mammary tumors and 60% of male breast carcinomas [32]. PRL has an essential role in the upregulation of the PRLr promoter, which involves the requisite participation of E2/ER α at the PRL promoter along with STAT5a [33].

Other receptors that play a key role in breast cancer tumorigenesis are EGFR (epidermal growth factor receptor) and HER2. EGF released by the stromal microenvironment surrounding the breast tumor activates signaling cascades that overlap with PRLr signaling cascades upon activation with PRL secreted by breast tumor cells. PRL stimulates HER2 and EGFR signaling pathways via JAK2. EGF/EGFR also activates STAT5 signaling indirectly via s-SRC. This crosstalk between receptors can increase progression of breast tumor and endocrine resistance (Fig. 5) [34].

PRLr, EGFR and HER2 signaling in breast cancer (adapted from Kavarthapu R, Anbazhagan R, Dufau ML. Crosstalk between PRLR and EGFR/HER2 signaling pathways in breast cancer. Cancers (Basel) (2021) 13(18):4685). EGF is released by stromal microenvironment surrounding the breast tumor and activates signaling cascades that overlap with PRLr signaling cascades. PRLr is activated by the PRL secreted by breast tumor cells. PRL stimulates HER2 and EGFR signaling pathways via JAK2. EGF EGFR activates STAT5 signaling indirectly via s-SRC. Adapter proteins: SOS, SHC, GRB2. Legend: EGF epidermal growth factor, EGFR epidermal growth factor receptor, PLRr prolactin receptor, SRC Src protein-tyrosine kinase, SHC SHC-transforming protein, SOS son-of-sevenless protein, GRB2 growth factor receptor bound protein 2, MAPK/ERK classical mitogen-activated protein kinase pathway, FAK focal adhesion kinase

Another event that contributes to the progression and motility of human breast cancer is the activation of the VAV family of guanine nucleotide exchange factors. The PRL-mediated activation of Nek3 contributes differentially to VAV2 signaling pathways involving Rac1 and signal transducer and activator of transcription 5 and implicates Nek3 during PRL-mediated actions in breast cancer [35].

In conclusion, more studies are needed to understand the mechanisms that regulate PRLr expression and function, but the causal role of the PRLr signaling axis in the pathogenesis of breast carcinoma is well established. A possible clinical application should encourage research in this area. On the basis of the observation that, in several immunohistochemical studies of patients with breast carcinoma, PRLr is expressed at high levels, the evaluation of PRLr expression should be considered in these patients and should be mandatory in patients diagnosed with PRL-secreting PitNETs. The impact of PRLr on prognosis is still under debate, but some studies have shown that PRLr can be a predictor of a favorable prognosis. Our patient experienced favorable evolution after breast cancer treatment concurrently with normalization of prolactin levels under cabergoline treatment. This case is intriguing and provides new evidence that resistant PRL-secreting PitNETs can be associated with the development of breast cancer. The patient had a history of breast masses that have undergone changes over the years and developed into tumor masses. The patient history of breast surgery before the prolactinoma diagnosis, and the high persistent PRL values despite the treatment are factors that have increased the risk of breast carcinoma development.