Prolactin: The Third Hormone in Breast Cancer

Abstract

Prolactin coordinates with the ovarian steroids to orchestrate mammary development and lactation, culminating in nourishment and an increasingly appreciated array of other benefits for neonates. Its central activities in mammary epithelial growth and differentiation suggest that it plays a role(s) in breast cancer, but it has been challenging to identify its contributions, essential for incorporation into prevention and treatment approaches. Large prospective epidemiologic studies have linked higher prolactin exposure to increased risk, particularly for ER+ breast cancer in postmenopausal women. However, it has been more difficult to determine its actions and clinical consequences in established tumors. Here we review experimental data implicating multiple mechanisms by which prolactin may increase the risk of breast cancer. We then consider the evidence for role(s) of prolactin and its downstream signaling cascades in disease progression and treatment responses, and discuss how new approaches are beginning to illuminate the biology behind the seemingly conflicting epidemiologic and experimental studies of prolactin actions across diverse breast cancers.

Keywords: HER2+ breast cancer; STAT 5 transcription factor; breast cancer; luminal breast cancer; mammary cancer; prolactin (PRL); triple negative breast cancer.

Figure 1

Studies of human samples and experimental models have shown that PRL can act on multiple target cells within the mammary environment, including not only epithelia, but also stromal cells, including immune and fibroblastic cell subpopulations. Although its effects on epithelia are best understood in the context of breast cancer, its actions on stromal targets which have been defined in other systems would also be predicted to increase the risk for breast cancer. See Section 2.2 for details.

Figure 2

PRL can initiate multiple signaling cascades in established cancers, which can result in different biological outcomes. Determination of the repertoire of PRL signals can be modulated by multiple factors, including properties of the ECM. In ER+ cell lines, the stiffness and density of the extracellular matrix (ECM) strongly influences the balance of these signals: in stiff matrices, PRL signals are shifted away from the canonical JAK2/STAT5A pathway, and toward FAK/SFK/ERK1/2. This shift permits PRL to drive proliferation, invasion, and resistance to tamoxifen (OHT), and further remodel collagen fibers in the ECM. These experimental findings support the clinical observations that ER+ cancers with regions of aligned collagen perpendicular to the tumor boundary have a worse prognosis, and that activated STAT5A is strongly linked to more differentiated cancers and tamoxifen sensitivity. See Section 3.4 for details.

Figure 3

PRLR is expressed on a substantial subset of breast cancers across the major subtypes. The outcome of PRL signals may vary considerably, driving either differentiation or aggression, depending on tumor cell intrinsic properties (PRLR expression, available downstream signaling cascades) as well as extrinsic factors (ECM characteristics, hormone/growth factor milieu), as illustrated above. See Section 3 for details.